EMOTE: Oral Enoximone in Intravenous Inotrope-Dependent Subjects
EMOTE: Oral Enoximone in Intravenous Inotrope-Dependent Subjects
Presenter: Arthur M. Feldman, MD, PhD, Jefferson Medical College (Philadelphia, Pennsylvania)
The type-III phosphodiesterase (PDE-III) inhibitor enoximone is a positive inotrope that also causes vasodilation; both properties could potentially be therapeutically useful in the treatment of heart failure. The oral capsule formulation of enoximone is in clinical evaluation for treating the following indications in chronic heart failure:
It is well known that patients with advanced heart disease often require frequent hospitalizations and/or palliative therapy with continuous or intermittent IV inotropic therapy. Unfortunately, IV inotropic therapy is associated with substantial morbidity (eg, line infections, thrombosis), possible increases in mortality, and high cost of protracted hospitalization stays.
In March 2004, preliminary results of the first phase 3 trial with enoximone capsules were announced. The Oral Enoximone in Intravenous Inotrope-Dependent Subjects (EMOTE) study failed to meet its primary endpoint -- successful weaning of patients off IV inotrope therapy at 30 days -- but it reached a number of secondary goals for periods over 30 days, and the mean number of days that patients required IV inotrope therapy was significantly reduced in those who were taking enoximone.
The main results of EMOTE were presented in detail at this year's Heart Failure Society of America Annual Scientific Meeting.
Study Design
EMOTE investigated whether low-dose oral enoximone can effectively support cardiac function in IV inotrope-dependent advanced heart failure patients, thereby alleviating the need for IV inotropic support. The primary endpoint was to determine whether low-dose oral enoximone can alleviate the need for IV inotropes in the short term, as defined by the primary outcome variable of alive and free of IV inotropes assessed at 30 days post scheduled weaning. The main secondary endpoint was to assess the efficacy, safety, and tolerability of oral enoximone in the same patient population over 26 weeks, as determined by the primary outcome variable assessed at later time points. The major safety measure was all-cause mortality, and all analyses were by intention to treat.
Patients and Treatment
A total of 201 patients were enrolled in EMOTE, all of whom met the following selected inclusion criteria:
Patients were randomized to placebo or enoximone (25/50 mg 3 times daily if on intermittent inotrope or 50/75 mg for 1 week followed by 25/50 mg 3 times daily if on continuous inotrope, doses dependent on body weight).
There were no differences in baseline patient characteristics between the 2 treatment groups, except that there were more women in the placebo group than in the enoximone group, which did not affect the outcome. In both groups, there was a mean of 2.7 hospitalizations during the previous 12 months, mean LVEF was 19%, LVEdD was 7.0 cm, and systolic blood pressure was 102 mm Hg.
Results
Of the patients randomized, 106 completed the study, 85 of whom were enrolled in an open-label extension protocol.
The primary endpoint, successful weaning at 30 days, was achieved by 61% of patients in the enoximone-treated group and 51% in the placebo-treated group (Table 1). This trend did not reach statistical significance (P = .171). The high placebo success rate was notably higher than the 25% sample size calculation assumed at the start of the study.
Table 1. Primary Endpoint Analysis
*Protocol-specified primary analyses by Cochran-Mantel-Haenszel test
Adjusted for etiology and continuous/intermittent iv inotrope therapy
The first secondary endpoint, analysis of the primary variable of time to death or re-initiation of IV inotrope therapy demonstrated benefit in favor of enoximone vs placebo for the 60-day and 90-day periods, with 39% and 31% risk reductions, respectively, but not for the 30-day and 182-day periods (31% and 25% risk reductions, respectively) (Table 2).
Table 2. Time to Event Analysis (Kaplan-Meier)
CI = confidence interval; HR = hazard ratio
Wilcoxon analysis of 2 other secondary endpoints showed a risk reduction associated with enoximone of 32% in the mean time to death or re-initiation of IV inotrope therapy (P = .042) and 42% in the total number of days on inotrope therapy (P = .049).
Safety
The safety results demonstrated no statistically significant difference in serious adverse events or mortality between the groups receiving placebo or enoximone capsules. A total of 38/101 patients died in the enoximone-treated group compared with 31/100 patients in the placebo-treated group (HR 1.270, 95% CI 0.790-2.041, P = .323). Most deaths were due to cardiovascular causes (Table 3). In the enoximone group, fewer sudden cardiovascular deaths were seen, but more nonsudden deaths were reported; by 2 × 2 comparison, this difference was statistically significant.
Table 3. Deaths by Category and Treatment
*2×2 comparison
Time to death among the patients on study medication or who had discontinued study medication within 48 hours of death did not differ between the groups, with 15 and 16 deaths in the enoximone and placebo groups, respectively (HR 0.962, 95% CI 0.476-1.946, P = .914).
A small increase in vomiting and diarrhea was seen in the enoximone group, leading to withdrawal of study medication in 3 patients. This was not unexpected, as these are common adverse events associated with enoximone. However, marked reductions were seen in both sepsis and anemia in the enoximone group, attributable to decreased use of indwelling catheters.
Investigators' Conclusions and Other Developments in Enoximone Treatment for Heart Failure
These results and safety profile indicate that low-dose oral enoximone can replace IV inotropic therapy in a substantial portion of patients with "ultra advanced" heart failure.
Three additional randomized, double-blind, placebo-controlled phase 3 clinical trials are evaluating the safety and efficacy of enoximone capsules (doses of 25 or 50 mg 3 times daily) in the long-term treatment of patients with advanced chronic heart failure.
The Studies of Oral Enoximone Therapy In Advanced Heart Failure (ESSENTIAL) I will track the time from randomization to cardiovascular hospitalization or death for each patient as the primary endpoint in approximately 900 patients with NYHA Class III and IV chronic heart failure who are being treated with beta-blockers and other therapies according to current guidelines. On average, patients will receive treatment for at least 12 months. This trial is being conducted in North and South America. Patient enrollment began in February 2002 and was completed in May 2004. ESSENTIAL II is identical in design and size to ESSENTIAL I but is being conducted in Western and Eastern Europe. Patient enrollment began in April 2002 and was completed in May 2004.
The Enoximone Plus Metoprolol in Subjects With Advanced Chronic Heart Failure (EMPOWER) trial will treat approximately 175 patients for 26-36 weeks with NYHA Class III/IV chronic heart failure with either placebo, extended-release metoprolol, or extended-release metoprolol in combination with enoximone capsules. The primary objective of this study is to determine whether enoximone capsules can increase the tolerability to metoprolol in patients previously shown to be intolerant to beta-blocker treatment. Patient enrollment began in September 2003.
Results of the ESSENTIAL trials, with support from EMOTE and EMPOWER, are considered pivotal for submission for regulatory approval of enoximone capsules in the United States and Europe.
Reference
The type-III phosphodiesterase (PDE-III) inhibitor enoximone is a positive inotrope that also causes vasodilation; both properties could potentially be therapeutically useful in the treatment of heart failure. The oral capsule formulation of enoximone is in clinical evaluation for treating the following indications in chronic heart failure:
Symptomatic relief;
Reduction in the frequency of hospitalizations, by delaying additional episodes of acute decompensated heart failure; and
Weaning patients with severe heart failure who are currently dependent on intravenous (iv) inotropic therapy from those agents, thus allowing them to leave the hospital.
It is well known that patients with advanced heart disease often require frequent hospitalizations and/or palliative therapy with continuous or intermittent IV inotropic therapy. Unfortunately, IV inotropic therapy is associated with substantial morbidity (eg, line infections, thrombosis), possible increases in mortality, and high cost of protracted hospitalization stays.
In March 2004, preliminary results of the first phase 3 trial with enoximone capsules were announced. The Oral Enoximone in Intravenous Inotrope-Dependent Subjects (EMOTE) study failed to meet its primary endpoint -- successful weaning of patients off IV inotrope therapy at 30 days -- but it reached a number of secondary goals for periods over 30 days, and the mean number of days that patients required IV inotrope therapy was significantly reduced in those who were taking enoximone.
The main results of EMOTE were presented in detail at this year's Heart Failure Society of America Annual Scientific Meeting.
Study Design
EMOTE investigated whether low-dose oral enoximone can effectively support cardiac function in IV inotrope-dependent advanced heart failure patients, thereby alleviating the need for IV inotropic support. The primary endpoint was to determine whether low-dose oral enoximone can alleviate the need for IV inotropes in the short term, as defined by the primary outcome variable of alive and free of IV inotropes assessed at 30 days post scheduled weaning. The main secondary endpoint was to assess the efficacy, safety, and tolerability of oral enoximone in the same patient population over 26 weeks, as determined by the primary outcome variable assessed at later time points. The major safety measure was all-cause mortality, and all analyses were by intention to treat.
Patients and Treatment
A total of 201 patients were enrolled in EMOTE, all of whom met the following selected inclusion criteria:
New York Heart Association (NYHA) Class III or IV
Intravenous inotrope dependent (confirmed by "gatekeeper")
Continuous: dobutamine or milrinone for ≥ 5 days, evidence of deterioration on reducing dose or attempted wean, or attempted wean
Intermittent: dobutamine ≥ 2 mcg/kg/min or milrinone ≥ 0.5 mcg/kg/min for ≥ 6 hours ≥ 1/week for ≥ 4 weeks
Left ventricular ejection fraction (LVEF) ≤ 25%
Left ventricular end-diastolic dimension (LVEdD) ≥ 5.4 cm or 2.7 cm/m
Conventional background therapy, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker required
Patients were randomized to placebo or enoximone (25/50 mg 3 times daily if on intermittent inotrope or 50/75 mg for 1 week followed by 25/50 mg 3 times daily if on continuous inotrope, doses dependent on body weight).
There were no differences in baseline patient characteristics between the 2 treatment groups, except that there were more women in the placebo group than in the enoximone group, which did not affect the outcome. In both groups, there was a mean of 2.7 hospitalizations during the previous 12 months, mean LVEF was 19%, LVEdD was 7.0 cm, and systolic blood pressure was 102 mm Hg.
Results
Of the patients randomized, 106 completed the study, 85 of whom were enrolled in an open-label extension protocol.
The primary endpoint, successful weaning at 30 days, was achieved by 61% of patients in the enoximone-treated group and 51% in the placebo-treated group (Table 1). This trend did not reach statistical significance (P = .171). The high placebo success rate was notably higher than the 25% sample size calculation assumed at the start of the study.
Table 1. Primary Endpoint Analysis
| Event Category | Placebo (n = 100) |
Enoximone (n = 101) |
Nominal (Unadjusted) P Value |
P Value Adjusted for Etiology* |
P Value Double Adjusted |
|---|---|---|---|---|---|
| Weaned and alive at 30 days |
51 (51%) |
62 (61%) |
.138 | .171 | .113 |
| Sample size assumptions | 25 (25%) |
50 (50%) |
< .044 | < .044 | < .044 |
Adjusted for etiology and continuous/intermittent iv inotrope therapy
The first secondary endpoint, analysis of the primary variable of time to death or re-initiation of IV inotrope therapy demonstrated benefit in favor of enoximone vs placebo for the 60-day and 90-day periods, with 39% and 31% risk reductions, respectively, but not for the 30-day and 182-day periods (31% and 25% risk reductions, respectively) (Table 2).
Table 2. Time to Event Analysis (Kaplan-Meier)
| Time Period | HR | 95% CI | P Value |
|---|---|---|---|
| 0-30 days | 0.699 | 0.457-1.070 | .098 |
| 0-60 days | 0.617 | 0.429-0.887 | .009 |
| 0-90 days | 0.691 | 0.493-0.968 | .031 |
| 0-182 days | 0.757 | 0.551-1.040 | .085 |
Wilcoxon analysis of 2 other secondary endpoints showed a risk reduction associated with enoximone of 32% in the mean time to death or re-initiation of IV inotrope therapy (P = .042) and 42% in the total number of days on inotrope therapy (P = .049).
Safety
The safety results demonstrated no statistically significant difference in serious adverse events or mortality between the groups receiving placebo or enoximone capsules. A total of 38/101 patients died in the enoximone-treated group compared with 31/100 patients in the placebo-treated group (HR 1.270, 95% CI 0.790-2.041, P = .323). Most deaths were due to cardiovascular causes (Table 3). In the enoximone group, fewer sudden cardiovascular deaths were seen, but more nonsudden deaths were reported; by 2 × 2 comparison, this difference was statistically significant.
Table 3. Deaths by Category and Treatment
| Category | Placebo n (%) |
Enoximone n (%) |
P
Value |
|---|---|---|---|
| Cardiovascular | 26 (26.0) | 34 (33.6) | .28 |
| Sudden | 11 (42.3) | 6 (17.6) | .046* |
| Nonsudden | 15 (57.7) | 28 (82.4) | |
| Vascular | 1 (1.0) | 0 (0) | |
| Noncardiovascular/vascular | 3 (3.0) | 1 (1.0) | |
| Unknown cause | 1 (1.0) | 3 (3.0) | |
| Totals | 31 (31.0) | 38 (37.6) |
Time to death among the patients on study medication or who had discontinued study medication within 48 hours of death did not differ between the groups, with 15 and 16 deaths in the enoximone and placebo groups, respectively (HR 0.962, 95% CI 0.476-1.946, P = .914).
A small increase in vomiting and diarrhea was seen in the enoximone group, leading to withdrawal of study medication in 3 patients. This was not unexpected, as these are common adverse events associated with enoximone. However, marked reductions were seen in both sepsis and anemia in the enoximone group, attributable to decreased use of indwelling catheters.
Investigators' Conclusions and Other Developments in Enoximone Treatment for Heart Failure
These results and safety profile indicate that low-dose oral enoximone can replace IV inotropic therapy in a substantial portion of patients with "ultra advanced" heart failure.
Three additional randomized, double-blind, placebo-controlled phase 3 clinical trials are evaluating the safety and efficacy of enoximone capsules (doses of 25 or 50 mg 3 times daily) in the long-term treatment of patients with advanced chronic heart failure.
The Studies of Oral Enoximone Therapy In Advanced Heart Failure (ESSENTIAL) I will track the time from randomization to cardiovascular hospitalization or death for each patient as the primary endpoint in approximately 900 patients with NYHA Class III and IV chronic heart failure who are being treated with beta-blockers and other therapies according to current guidelines. On average, patients will receive treatment for at least 12 months. This trial is being conducted in North and South America. Patient enrollment began in February 2002 and was completed in May 2004. ESSENTIAL II is identical in design and size to ESSENTIAL I but is being conducted in Western and Eastern Europe. Patient enrollment began in April 2002 and was completed in May 2004.
The Enoximone Plus Metoprolol in Subjects With Advanced Chronic Heart Failure (EMPOWER) trial will treat approximately 175 patients for 26-36 weeks with NYHA Class III/IV chronic heart failure with either placebo, extended-release metoprolol, or extended-release metoprolol in combination with enoximone capsules. The primary objective of this study is to determine whether enoximone capsules can increase the tolerability to metoprolol in patients previously shown to be intolerant to beta-blocker treatment. Patient enrollment began in September 2003.
Results of the ESSENTIAL trials, with support from EMOTE and EMPOWER, are considered pivotal for submission for regulatory approval of enoximone capsules in the United States and Europe.
Reference
Feldman AM. Oral enoximone in intravenous inotrope-dependent subjects (EMOTE): a phase III, randomized, double-blind, placebo-controlled parallel study. Late-Breaking and Recent Clinical Trials. Presented at the 8th Annual Scientific Meeting of the Heart Failure Society of America; September 12-15, 2004; Toronto, Ontario, Canada.
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